Trimethylamine N-oxide induces non-alcoholic fatty liver disease by activating the PERK

• Published in: Toxicology letters 2024-10, Vol.400, p.93-103
• Main Authors: Yang, Bingmo, Tang, Guomin, Wang, Mengting, Ni, Yifan, Tong, Jiali, Hu, Chunyan, Zhou, Ming, Jiao, Kailin, Li, Zhong
• Format: Article
• Language: English
• Subjects: Endoplasmic reticulum stress; Non-alcoholic fatty liver disease; Trimethylamine N-oxide
• ISSN: 0378-4274; 1879-3169; 1879-3169
• DOI: 10.1016/j.toxlet.2024.08.009

Nonalcoholic fatty liver disease (NAFLD) is a liver disease causing different progressive pathological changes. Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, is a specific agonist of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, one of the endoplasmic reticulum stress (ERS) pathways. TMAO has been associated with the occurrence and development of NAFLD based on the results of previous studies, but whether the simple consumption of TMAO can directly induce NAFLD and its underlying mechanism remain unclear. To investigate this question, we constructed an animal model in which adult male zebrafish were fed a controlled diet containing 1 % or 3 % TMAO for 20 weeks. Eventually, we observed that TMAO caused lipid accumulation, inflammatory infiltration, liver injury and liver fibrosis in zebrafish livers; meanwhile, the PERK signaling pathway was activated in the zebrafish livers. This finding was further confirmed in HepG2 cells and hepatic stellate cells models. In conclusion, this study found that TMAO directly induced different pathological states of NAFLD in zebrafish liver, and the activation of PERK pathway is an important mechanism, which may provide crucial strategies for the diagnosis and treatment of NAFLD. •Hepatic steatosis caused by TMAO mainly occurred at the initial stage of the lesion.•TMAO provoked NASH and promoted liver fibrotic pathological changes in zebrafish.•The activation of PERK pathway was involved in TMAO-induced NAFLD.